(a) Field of the Invention
This invention relates to improvements in the process for preparing 1-benzyl-4-cyano-4-phenylpiperidine or hydrochloride acid-addition salt thereof, an intermediate for the preparation of meperidine, namely, ethyl 1-methyl-4-phenylpiperidine-4-carboxylate, commercially available in the form of its hydrochloride as an analgesic, spasmolytic and sedative
(b) Information Disclosure Statement
O. Eisleb in Example 2 of U.S. Patent 2,167,351, issued July 25, 1939, shows the preparation of 1-benzyl-4-phenylpiperidine-4-carbonitrile hydrochloride, m.p. 259.degree.-260.degree. C., as an intermediate for normeperidine, namely, ethyl 4-phenylpiperidine-4-carboxylate, by first reacting benzyl chloride with N,N-bis(2-hydroxyethyl)amine to produce N,N-bis(2-hydroxyethyl)benzylamine, next reacting the latter compound with thionyl chloride to produce N,N-bis(2-chloroethyl)benzylamine and isolating it in free base form as "an oil of feebly brownish color"; and then heating N,N-bis(2-chloroethyl)benzylamine with benzyl cyanide (same as phenylacetonitrile) in toluene in the presence of sodium amide (same as sodamide).
M. K. Deutch and H. W. Stobbe in Example 1 of U.S. Pat. No. 2,653,156, issued Sept. 22, 1953, show the preparation in 52% yield of N,N-bis(2-hydroxyethyl)benzylamine (as an intermediate for preparing its caprylate ester) by the action of one mole of benzyl chloride on one mole of N,N-bis(2-hydroxyethyl)amine "in the presence of potassium carbonate" and subsequent distillation under vacuum. The potassium carbonate is said to serve "as an acid acceptor and may be replaced by any suitable alkaline material capable of combining with the chlorine of the benzyl chloride, for example, alkali metal carbonates or bicarbonates such as sodium carbonate or bicarbonate, triethanolamine or pyridine".
E. Szarvasi et al., Eur. J. Med. Chem. Chim. Ther. 11(2), 115-24 (1976), in a paper pertaining to the preparation of spiro[piperidine-4,6-thiazolo[3,2-a]pyrimidines], dines], thymoanaleptics and blood platelet aggregation inhibitors, show inter alia at page 123, 2nd column: (a) the preparation of N,N-bis(2-hydroxyethyl)benzylamine (compound no. 1e, Table VIIIa, p. 121) in 89% yield, m.p. 168.degree.-172.degree. C., by rapidly adding 0.5 mole of benzyl chloride (or bromide) to a mixture of 0.5 mole of N,N-bis(2-hydroxyethyl)amine, 0.55 mole (or more than two molar equivalents) of potassium carbonate and 500 cc of toluene kept at about 60.degree. to 70.degree. C., heating the reaction mixture to reflux for four hours, filtering off the inorganic salts and washing them with a little toluene, and distilling the filtrate; and, (b) the preparation of N,N-bis(2-chloroethyl)benzylamine hydrochloride (compound no. 2e, Table VIIa, p. 121) in 98% yield, m.p. 148.degree.- 150.degree. C., by the following procedure: To a solution of 0.295 mole of N,N-bis(2-hydroxyethyl)benzylamine in 225 cc of chloroform was added, so that the temperature was maintained between 30.degree. and 40.degree. C., a solution containing 0.710 mole of thionyl chloride in 50 cc of chloroform. The reaction mixture was refluxed for four hours; and, the precipitated hydrochloride of N,N-bis(2-chloroethyl)benzylamine was collected and recrystallized from ethanol.
W. S. Gump and E.J. Nikaivitz in Example 3 of U.S. Pat. No. 2,504,977 issued April 25, 1950, show the reaction of 190 g of benzyl chloride with 315 g of N,N-bis(2-hydroxyethyl)amine at 100-125.degree. C. for nine hours followed by addition of sufficient saturated potassium carbonate to neutralize "the formed hydrochlorides" and continued stirring of the mixture for thirty minutes at 90.degree. C. The separated oil in isopropyl ether and ethanol was dried and distilled twice to produce 162 g (54.3% yield) of pure N,N-bis(2-hydroxyethyl)benzylamine. A 97 g portion of N,N-bis(2-hydroxyethyl)benzylamine was converted into 115 g (85.7% yield) of N,N-bis(2-chloroethyl)benzylamine hydrochloride (46.5% yield based on benzyl chloride) by adding dropwise with stirring 120 g of thionyl chloride in chloroform to a cooled (ice bath) chloroform solution of N,N-bis(2-hydroxyethyl)benzylamine, and then isolating the product and converting it to its hydrochloride salt.
D. Thompson and P. C. Reeves, J. Heterocyclic Chem. 20, 771-2 (May-June 1983), show inter alia the reaction of phenylacetonitrile with N,N-bis(2-chloroethyl)benzylamine in 50% aqueous sodium hydroxide solution in the presence of a catalytic amount of various phase-transfer catalysts including benzyltriethylammonium chloride, tricaprylmethylammonium chloride, trialkyl (C.sub.8 -C.sub.10)methylammonium chloride, dicyclohexyl-18-crown-6, and hexadecyl tributylphosphonium bromide. These authors report:
"All of these catalysts are active, but the phosphonium catalyst is vastly superior to the others for this specific application. It produces high yields of the desired compounds in a short reaction time with only trace amounts of undesired by-products being formed." PA1 "The recent advent of phase-transfer catalysis has provided attractive alternatives to the use of hazardous bases such as sodium amide and anhydrous aprotic solvents. It has been demonstrated that phenylacetonitrile can be alkylated under phase-transfer conditions with 1,5-dibromopentane and bis(2-chloroethyl) ether to yield the corresponding six-membered rings [M. Makoska and B. Serafinowa, Rozc. Chem. 40, 1647 (1966)]. Attempts to extend this technique to the synthesis of nitrogen heterocycles have been plagued by very low yields [B. Gutowska, Acta Pol. Pharm. 30, 109 (1973) and L. Rylski, F. Gajewski and Z. Kamonski, ibid., 31, 577(1974)].
These authors also state:
Gutkowska, Acta Pol. Pharm. 30, 109-113 (1973), shows the reaction of N,N-bis(2-chloroethyl)-n-butylamine with phenylacetonitrile in the presence of 50% aqueous sodium hydroxide solution and benzyltriethylammonium chloride as catalyst to produce 1-n-butyl-4-cyano-4-phenylpiperidine hydrochloride (30% yield).
L. Rylski, F. Gajewski and Z. Kamonski, Acta Pol. Pharm. 31, 577-582 (1974), show two methods for the conversion of N,N-bis(2-chloroethyl)benzylamine by reaction with phenylacetonitrile to produce 1-benzyl-4-cyano4-phenylpiperidine hydrochloride, the first method in a sodium hydroxide-toluene system resulting in a 63% yield of product melting at 253.degree.-254.degree. C. and the second method in a catalytic process using benzyltriethylammonium chloride in 50% aqueous sodium hydroxide resulting in a 61% yield of product melting at 254.degree.-255.degree. C. (Eisleb, supra, 259.degree.-260.degree. C.).
Heretofore, 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride was produced commercially by first refluxing benzyl chloride in toluene with bis(2-hydroxyethyl)amine at about 105.degree. C. to 115.degree. C. for no less than 24 hour preferably 48 hours, and then in a second step adding thionyl chloride to the resulting N,N-bis(2-hydroxyethyl)benzylamine in toluene, quenching the reaction mixture with water followed by addition of aqueous sodium hydroxide solution, separating the toluene layer and azeotroping it to dryness to obtain a toluene solution containing about 70% yield (based on benzyl chloride) of N,N-bis(2-chloroethyl)benzylamine, and then in a third step treating portionwise a toluene solution of the latter and phenylacetonitrile with sodamide, quenching the reaction mixture with water, separating the toluene solution, distilling off in vacuo the toluene, dissolving the residual oil in methanol, acidifying the methanol solution with concentrated hydrochloric acid, collecting the precipitate, washing it with cold methanol and drying it to produce about a 57% yield [based on benzyl chloride] of 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride. Analysis of the reaction mixture resulting from the first step of this preparation by gas chromatography/mass spectrography (GC/MS) revealed the presence of three major peaks in the ratio by weight of 53:13:16 (I:II:III) found to be respectively the desired intermediate, N,N-bis(2-hydroxyethyl)benzylamine (I) and two by-products, identified as N,N-dibenzyl-N-(2-hydroxyethyl)amine (II) and N-benzyl-N-(2-benzyloxyethyl)-N-(2-hydroxyethyl)amine (III). Comparable analysis of the second step of this preparation revealed the presence of another by-product, namely N-benzylmorpholine (about 5-10%). Virtual elimination of the formation of these three by-products is accomplished by the improved process of the invention.